1.Individualized Treatment for Patients With Familial Hypercholesterolemia
Hayato TADA ; Masayuki TAKAMURA ; Masa-aki KAWASHIRI
Journal of Lipid and Atherosclerosis 2022;11(1):39-54
Familial hypercholesterolemia (FH) is one of the most common and, therefore, important inherited disorders in preventive cardiology. This disease is mainly caused by a single pathogenic mutation in the low-density lipoprotein receptor or its associated genes. Moreover, it is correlated with a high risk of cardiovascular disease. However, the phenotype severity even in this monogenic disease significantly varies. Thus, the current study aimed to describe FH and its importance and the factors (inherited and acquired) contributing to differences in phenotype severity. Different lipid-modification therapies according to these factors can lead to individualized treatments, which are also essential in the general populations.
2.Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia
Nobuko KOJIMA ; Hayato TADA ; Akihiro NOMURA ; Soichiro USUI ; Kenji SAKATA ; Kenshi HAYASHI ; Atsushi NOHARA ; Akihiro INAZU ; Masa-aki KAWASHIRI ; Masayuki TAKAMURA
Journal of Lipid and Atherosclerosis 2024;13(1):53-60
Objective:
Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia.
Methods:
This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targetedsequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL.
Results:
Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5–17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5–4.1] µg/mL) in 14 individuals.
Conclusion
The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.
3.Phenotypic diversity of hereditary sensory and autonomic neuropathy type IE: a case series and review of the literature
Noriyuki Miyaue ; Yuki Yamanishi ; Satoshi Tada ; Rina Ando ; Hayato Yabe ; Noriko Nishikawa ; Masahiro Nagai ; Hiroshi Takashima ; Masahiro Nomoto
Neurology Asia 2019;24(1):15-20
Objective: DNA methyltransferase 1 (DNMT1) is crucial to maintaining methylation during DNA
replication and DNA repair. DNMT1 mutations have been identified in two neurological syndromes,
including hereditary sensory and autonomic neuropathy type IE (HSAN IE) with dementia and
hearing loss and autosomal dominant cerebellar ataxia, deafness and narcolepsy. It is likely that
DNMT1 mutations lead to various symptoms of the central and peripheral nervous system. The aim
of this study was to examine the clinical characteristics, especially the initial symptoms, in the cases
of DNMT1 mutations. Methods: We investigated the clinical manifestation and examination findings
of four cases of HSAN IE from one family with the DNMT1 mutation c.1531Y>C (p.Try511His).
Results: All four cases exhibited sensory neuropathy, cerebellar ataxia, and hearing loss, all of which
were demonstrated by the audiograms. The initial symptoms of the four cases included hearing loss
(n=1), gait disturbance (n=1), and depressive mood (n=2). Depressive symptoms are reported in some
cases with HSAN IE, however, there are currently no published reports that describe them as primary
symptoms. The CSF orexin level was measured in three cases, revealing normal values in two cases
and intermediate values in one case, in which the patient exhibited rapid eye movement (REM) sleep
behavior disorder.
Conclusion: Our findings suggest that in cases with HSAN IE or the DNMT1 mutation, psychiatric
symptoms should be taken into account as one of the initial manifestations of the disease.